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Gary T Kinasewitz

Publications and source records attributed to Gary T Kinasewitz.

17 recordsLinked to original sources
PubMed2006

Rounded atelectasis with atypical computed tomography findings.

Rounded atelectasis is atelectasis of the peripheral part of the lung, typically in contact with thickened pleura, featuring characteristic computed tomography findings. In this case, a 61-year-old man with history of asbestos exposure presented with a right-middle-lobe nodule on chest radiograph, with computed tomography findings suspicious for neoplasm. The patient underwent surgical resection, which revealed rounded atelectasis. Our case raises a question about the sensitivity of radiographic criteria used in identifying rounded atelectasis, and it emphasizes the need to keep rounded atelectasis in the differential diagnosis of a single pulmonary nodule in a patient with a history of asbestos exposure.

Diagnosis, Differential↗
PubMed2005

Severe community-acquired pneumonia as a cause of severe sepsis: data from the PROWESS study.

OBJECTIVE: To investigate community-acquired pneumonia (CAP) as a cause of severe sepsis in the PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) trial and to evaluate the effect of drotrecogin alfa (activated) (DrotAA) in this subgroup. DESIGN: Retrospective analysis of the severe CAP subgroup in the PROWESS trial. SETTING: Tertiary care institutions in 11 countries. INTERVENTIONS: DrotAA (n = 850), 24 microg.kg.hr for 96 hrs, or placebo (n = 840). PARTICIPANTS: The 1,690 patients with severe sepsis enrolled in the PROWESS trial. MEASUREMENTS AND MAIN RESULTS: Patients were classified as having CAP if lung was the primary site of infection and if they were enrolled directly from home (private residence) with </=4 days in the hospital before receipt of study drug in the PROWESS trial. Survival at 28 days, hospital discharge, and 90 days was compared in DrotAA and placebo groups in the CAP subgroup of PROWESS and CAP subgroups based on disease severity. Of the 1,690 PROWESS patients, 35.6% (DrotAA, n = 324; placebo, n = 278) were classified as severe CAP. Of these severe CAP patients, 26.1% had Streptococcus pneumoniae infections. Within CAP, 79.1% were enrolled by the end of the second calendar day in the hospital, and approximately 90% of CAP patients were at high risk of death according to the Pneumonia Severity Index category. Based on their dependence on vasopressors, 59% of CAP patients were judged at high risk of death. Biomarkers of coagulation and inflammation were markedly abnormal in severe CAP patients. In severe CAP patients treated with DrotAA, a relative risk reduction in mortality of 28% was observed at 28 days, with a relative risk reduction in mortality of 14% observed at 90 days from the start of study drug infusion. The survival benefit was most pronounced in severe CAP patients with S. pneumoniae and in severe CAP patients at high risk of death as indicated by Acute Physiology and Chronic Health Evaluation II score of >/=25, Pneumonia Severity Index score of >/=4, or CURB-65 (confusion, urea, respiratory rate, blood pressure, age) score of >/=3. CONCLUSIONS: CAP associated with a high Pneumonia Severity Index score, bacteremia, or an intense coagulation and inflammatory response requiring intensive care unit care were indicators of a high risk of death from severe sepsis. In patients with severe sepsis resulting from CAP, a readily identifiable disease, DrotAA, improved survival compared with placebo.

APACHE↗
PubMed2005

Prognostic value of a simple evolving disseminated intravascular coagulation score in patients with severe sepsis.

OBJECTIVE: We postulated that the coagulopathy initiated by the inflammatory response to severe sepsis would be reflected by changes in the platelet count and prothrombin time that convey prognostic information. To examine this hypothesis, we looked at the utility of a simple evolving disseminated intravascular coagulation (DIC) score that awarded 1 point for each of the following: a) an absolute platelet count <100 x 10/L; b) a prothrombin time >15.0 secs; c) a 20% decrease in platelets; and d) a >0.3-sec increase in prothrombin time in predicting outcome in patients with severe sepsis. DESIGN: Prospective observational study. SETTING: Intensive care units of university medical center. PATIENTS: Patients were 163 critically ill severe sepsis patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients were clinically classified as having capillary leak syndrome (n = 24), multiple organ failure with death from sepsis (n = 37), or multiple organ failure with recovery (n = 57) or as well (n = 45) if they showed rapid improvement in their modified Multiple Organ Dysfunction Syndrome (MODS) score (which did not score for thrombocytopenia). Patients with capillary leak syndrome had the highest Acute Physiology and Chronic Health Evaluation II score, modified MODS, and prothrombin time and the lowest platelet counts, whereas well patients had the most normal values. The simple evolving DIC score increased with worsening clinical class and was associated with worsening organ failure (increased modified MODS). Mortality rate increased from 10% for a simple evolving score of 0 to 73% for a score of 4 (p < .01). Overall, 86% of those with a score < or =1 survived, whereas 85% of those with a score of > or =2 developed multiple organ failure and half of them died from sepsis. CONCLUSIONS: The simple evolving DIC score calculated in the first 48 hrs from two readily available global coagulation markers appears to reflect the severity of the underlying disorder. It can be easily calculated at the bedside and provides useful prognostic information for the patient with severe sepsis.

Adult↗
PubMed2005

Cough and spontaneous rupture of a normal spleen.

Rupture of the spleen is a relatively common complication of trauma and many systemic disorders affecting the reticuloendothelial system, including infections and neoplasias. A rare subtype of rupture occurring spontaneously and arising from a normal spleen was recognized as a distinct clinicopathologic entity. The pathogenesis is debated in the absence of external trauma or predisposing disease. It has been reported in association with apparently trivial insults such as vomiting. We report a case of a patient with spontaneous rupture of a normal spleen. Interestingly, it was observed after severe coughing.

Cough↗
PubMed2004

Universal changes in biomarkers of coagulation and inflammation occur in patients with severe sepsis, regardless of causative micro-organism [ISRCTN74215569].

INTRODUCTION: PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) was a phase III, randomized, double blind, placebo controlled, multicenter trial conducted in patients with severe sepsis from 164 medical centers. Here we report data collected at study entry for 1690 patients and over the following 7 days for the 840 patients who received placebo (in addition to usual standard of care). METHODS: Nineteen biomarkers of coagulation activation, anticoagulation, fibrinolysis, endothelial injury, and inflammation were analyzed to determine the relationships between baseline values and their change over time, with 28-day survival, and type of infecting causative micro-organism. RESULTS: Levels of 13 of the 19 biomarkers at baseline correlated with Acute Physiology and Chronic Health Evaluation II scores, and nearly all patients exhibited coagulopathy, endothelial injury, and inflammation at baseline. At study entry, elevated D-dimer, thrombin-antithrombin complexes, IL-6, and prolonged prothrombin time were present in 99.7%, 95.5%, 98.5%, and 93.4% of patients, respectively. Markers of endothelial injury (soluble thrombomodulin) and deficient protein C, protein S, and antithrombin were apparent in 72%, 87.6%, 77.8%, and 81.7%, respectively. Impaired fibrinolysis (elevated plasminogen activator inhibitor-1) was observed in 44% of patients. During the first 7 days, increased prothrombin time (which is readily measurable in most clinical settings) was highly evident among patients who were not alive at 28 days. CONCLUSION: Abnormalities in biomarkers of inflammation and coagulation were related to disease severity and mortality outcome in patients with severe sepsis. Coagulopathy and inflammation were universal host responses to infection in patients with severe sepsis, which were similar across causative micro-organism groups.

APACHE↗
PubMed2004

Infection-induced modulation of m1 and m2 phenotypes in circulating monocytes: role in immune monitoring and early prognosis of sepsis.

To monitor and better understand the immunoinflammatory sequelae in sepsis and septic shock, systemic and monocyte-related cytokine responses were evaluated in baboons with experimental peritonitis induced by an E. coli-laden fibrin clot. Despite similar bacterial inocula, considerable interindividual variability in clinical manifestation and outcome of infection was observed. Because monocytes and macrophages are a key component of innate immunity, we hypothesized that early polarization of distinct activation programs in circulating monocytes that culminates in the emergence of either classically (M1) or alternatively (M2) activated monocytes may underlie the observed susceptibility or resistance to infection. To test our hypothesis, we analyzed infection-induced expression of cytokine mRNAs in monocytes isolated from surviving and dead animals. Our data show that resistance to E. coli sepsis may well be associated with a mixed M1/M2 activation state of circulating monocytes, whereas M1 phenotype appeared to be prevailing in monocytes from animals that died. Together with data on systemic cytokine responses, the latter findings indicate that morbidity and mortality of animals with gram-negative sepsis may well result from an overwhelming proinflammatory response. Collectively, our data contribute to a better understanding of cytokine networking in the immunoinflammatory response to microbial infection and suggest M1/M2 immunophenotypic profiling of readily available circulatory monocytes for early prognosis of severe infections.

Animals↗
PubMed2003

Systemic host responses in severe sepsis analyzed by causative microorganism and treatment effects of drotrecogin alfa (activated).

Clinical trials with novel therapeutic agents for severe sepsis have suggested that patients might respond differently depending on causative microorganism. Data from a large, placebo-controlled trial of recombinant human drotrecogin alfa (activated) (DrotAA) were analyzed by type of causative microorganism for treatment-associated differences in mortality, coagulopathy, and inflammatory response. Compared with placebo, mortality rates associated with DrotAA were consistently reduced for each microorganism group (gram-positive bacteria, gram-negative bacteria, mixed bacteria, fungi, other, and unknown microbial etiology), with a stratified relative risk (RR) of 0.80 (95% confidence interval [CI], 0.69-0.94). The greatest reduction in the mortality rate was for Streptococcus pneumoniae infection (RR, 0.56; 95% CI, 0.35-0.88). Levels of coagulation and inflammation biomarkers varied with different pathogens at study entry. Results demonstrate that DrotAA, administered as an adjunct to standard anti-infective therapy, can improve the rate of survival for patients who develop severe sepsis regardless of causative microorganism.

Anti-Bacterial Agents↗
PubMed2003

Hepatic hydrothorax.

A hepatic hydrothorax is a pleural effusion that develops in a patient with cirrhosis and portal hypertension in the absence of cardiopulmonary disease. The pleural effusion is derived from ascitic fluid that enters the chest because of the negative pressure within the pleural space via defects in the diaphragm. The peritoneal-to-pleural flow of fluid can be demonstrated by nuclear scanning, even when the ascites is not clinically apparent. The pleural fluid usually has the characteristics of a transudate. However, an occasional patient with hepatic hydrothorax will develop spontaneous bacterial pleuritis manifest by increased pleural fluid neutrophils or a positive bacterial culture and will require antibiotic therapy. Treatment of the hydrothorax is directed at the underlying liver disease but a dyspneic patient can obtain relief from a thoracentesis or paracentesis. When medical therapy fails, liver transplantation is the treatment of choice. Both transjugular intrahepatic portosystemic shunting and thoracoscopic repair of diaphragmatic defects with pleural sclerosis can provide symptomatic relief, but the morbidity and mortality of these procedures are high because of the fragile nature of the patients.

Humans↗
PubMed2003

The clinical evaluation committee in a large multicenter phase 3 trial of drotrecogin alfa (activated) in patients with severe sepsis (PROWESS): role, methodology, and results.

OBJECTIVE: In the multinational PROWESS trial, drotrecogin alfa (activated) significantly reduced mortality rate in patients with severe sepsis compared with placebo. The use of large multiple-center trials can potentially complicate interpretation of results in severe sepsis populations because of variability in medical attitudes and practices and the frequency of confounding events such as protocol violations. The objective of this study was to perform a blinded, critical, integrated review of data from the 1,690 severe sepsis patients from 164 medical centers enrolled in the PROWESS trial using a Clinical Evaluation Committee. DESIGN: Blinded, critical, integrated review of data. SETTING: Participating sites. PATIENTS: The 1,690 severe sepsis patients from 164 medical centers enrolled in the PROWESS trial. INTERVENTIONS: We performed analyses of the optimal cohort, defined as patients who had full compliance with the protocol, had evidence of an infection, and received adequate anti-infective therapy. We also performed other analyses, including significant underlying disorders, life support measures, and causes of death. MEASUREMENTS AND MAIN RESULTS: The optimal cohort of 81.4% of the intention-to-treat population [drotrecogin alfa (activated), n = 695; placebo, n = 680] had similar baseline severity of illness between the two groups, a similar pharmacodynamic effect, and a relative risk of death estimate consistent with that observed in the overall PROWESS trial (0.83, 95% confidence interval 0.69-0.99 vs. 0.806, 95% confidence interval 0.69-0.94). A beneficial effect of drotrecogin alfa (activated) similarly was observed in patients with significant underlying disorders (0.73, 95% confidence interval 0.57-0.93) who were more severely ill and had a higher percentage of patients forgoing life-sustaining therapy. In contrast with the original investigator determinations, a benefit associated with drotrecogin alfa (activated) treatment in urinary tract infection adjudicated by the Clinical Evaluation Committee was observed. CONCLUSIONS: The survival benefit associated with drotrecogin alfa (activated) use was consistent with the results of the overall trial regardless of whether patients met criteria of the optimal cohort or had a significant underlying disorder.

APACHE↗
PubMed2003

Reduced neutrophil CD10 expression in nonhuman primates and humans after in vivo challenge with E. coli or lipopolysaccharide.

CD10, also known as neutral endopeptidase or CALLA, is a major metalloproteinase that regulates levels of biologically active peptides that initiate inflammatory, cardiovascular, and neurogenic responses. Relative tissue expression levels of CD10, its peptide substrates, and their receptors constitute the basic regulatory mechanism. Neutrophils contain abundant CD10 and are rapid responders to an inflammatory septic challenge. Expression of neutrophil surface antigens in response to inflammation was studied in the primate model of Escherichia coli-mediated sepsis and in human volunteers injected with lipopolysaccharide (LPS). There was a rapid and profound (up to 95%) reduced baboon neutrophil CD10 expression in response to E. coli injections of 5.71 x 106 CFU/kg to 2.45 x 109 CFU/kg that gradually resolved to preinjection levels. The reduction was both dose and time dependent. Reduced CD10 antigen on mature baboon neutrophils and bands was observed by immunohistochemistry. Human volunteers challenged with 4ng/kg LPS experienced transient chills, nausea, fever, and myalgia. Up to approximately 20% of their neutrophils had reduced CD10 expression, peaking at 2 to 8 h after injection. By 24 h, neutrophil CD10 expression resolved to preinjection levels. In contrast, in both the baboon and human studies, other neutrophil surface antigens were only slightly decreased (CD11a) or increased (CD11b, CD18, CD35, CD66b, and CD63). These data present the novel observation that neutrophil CD10 expression decreases significantly in response to in vivo inflammatory challenge. This decrease appears to be unique to CD10 and may contribute to a reduced regulation of bioactive peptides released in response to inflammatory challenge.

Animals↗
PubMed2003

Drotrecogin alfa (activated) (recombinant human activated protein C) reduces host coagulopathy response in patients with severe sepsis.

Drotrecogin alfa (activated) improved survival in patients with severe sepsis in PROWESS, a double-blind, study of 1690 adult patients randomized to drotrecogin alfa (activated) at 24 microg/kg/h (N=850) or placebo (N=840) infused for 96 hours. Pharmacodynamic effects of drotrecogin alfa (activated) were assessed with 15 prospectively defined systemic biomarkers of hemostasis, inflammation and endothelial injury. The last-observation-carried-forward (LOCF) method of imputation for missing observations was the prospectively defined statistical method. The results were also analyzed with only the observed values without imputation for missing data (repeated measures analysis). With both statistical methods, drotrecogin alfa (activated)-treated patients demonstrated antithrombotic (reduced markers of thrombin generation and accelerated normalization of anticoagulant factor, protein C and fibrinolytic factors) and anticoagulant (prolonged PT and APTT) effects compared with placebo. A profibrinolytic (reduction in plasminogen activator inhibitor-1) effect was significant only with the LOCF imputation method in observed case and percent change from baseline analyses. An anti-inflammatory (reduction in interleukin-6) effect was significant only with the LOCF imputation method in change from baseline and percent change from baseline analyses. Drotrecogin alfa (activated) is a new and promising agent for treatment of patients with severe sepsis. The extensive analysis of systemic biomarkers confirms the previously published antithrombotic effects. However, the present results using different statistical methods do not provide a strong basis for systemic anti-inflammatory or pro-fibrinolytic effects. These latter two effects may occur at the local or cellular level. The systemic biomarkers reported here might not be the most appropriate approach to demonstrate these potential effects of drotrecogin alfa (activated).

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2002

Risk-benefit analysis for drotrecogin alfa (activated).

An analysis of risks and benefits is an important component of patient care. Drotrecogin alfa (activated), the first approved cogin (a class of recombinant human coagulation inhibitors), provides a clear example of a treatment that requires a careful risk-benefit analysis. Treatment with this novel compound has been shown to reduce significantly the risk of death in patients with sepsis and acute organ dysfunction (severe sepsis). However, the drug is a natural antithrombotic that can increase the risk of bleeding in recipients. We will discuss bleeding and other potential risks associated with drotrecogin alfa (activated) treatment, as well as the survival benefits seen with the use of this therapy in patients with severe sepsis.

APACHE↗
PubMed2002

Duplication 15q in a patient with t(8;21) acute myeloblastic leukemia (M2).

We present unique chromosomal abnormalities found in a patient with acute myeloblastic leukemia (AML) of French-American-British subtype M2. The patient was referred for an evaluation of chromosomal anomaly associated with AML. She was found to have an abnormal karyotype 46,XX,t(8;21)(q22;q22), and a questionable dup(15)(q15q22) in the majority of cells analyzed. Two cells had the same chromosomal anomalies plus a duplicated derivative chromosome 21 [der(21)t(8;21)(q22;q22)]. These cytogenetic findings were confirmed by fluorescence in situ hybridization utilizing the appropriate DNA probes. To our knowledge, this is the first case report of a combination of the translocation between chromosomes 8 and 21, a duplication of chromosome 15 [dup(15)(q15q22), and a duplicated derivative chromosome 21 [der(21)t(8;21)(q22;q22)].

Adult↗
PubMed2002

Exudative effusions in congestive heart failure.

OBJECTIVES: Pleural effusions due to congestive heart failure (CHF) typically are transudates, but an occasional patient with CHF is found to have an exudate in the absence of an apparent cause other than CHF. We sought to determine the incidence and clinical significance of such exudative effusions. DESIGN: Patients with CHF and effusions seen during the 7-year period from January 1994 through December 2000 were identified from their hospital discharge diagnoses and radiographs, while those who had undergone thoracentesis were identified from a review of the laboratory logs. The presenting symptoms and clinical course were determined from a review of the medical records. The effect of RBC contamination on pleural fluid lactate dehydrogenase (LDH) levels was determined by measuring the LDH activity of mock pleural fluid containing known amounts of RBC. RESULTS: Seven hundred seventy patients had CHF with an effusion, but only 175 patients underwent a thoracentesis. In this select group, 86 patients had transudates and 89 had exudates. A noncardiac cause for the exudate was readily identified in 59 patients by hospital discharge, and 7 more patients had an etiology found during follow-up. Eleven of the remaining 23 patients had undergone coronary artery bypass graft (CABG) surgery > or = 1 year prior to presentation, and 50% of the effusions in patients who had undergone CABG surgery were exudates. Thus, CHF-related exudates were identified in only 12 patients, and in 4 of these patients the exudates could be explained by RBC contamination of the pleural fluid. The clinical presentation of patients with CHF-associated exudates was similar to that of CHF patients with transudates. CONCLUSION: In most patients who have CHF and an exudative effusion, there is a noncardiac cause for the pleural effusion. The high frequency of exudates in patients with a history of CABG indicates a persistent impairment in lymphatic clearance from the pleural cavity. Exudative effusions due solely to CHF are rare.

Aged↗
PubMed2002

The diagnosis and management of disseminated intravascular coagulation.

This review describes disseminated intravascular coagulation (DIC) as a syndrome in which hemostatic factors are activated. The syndrome ranges in severity from a decompensated coagulopathy (overt-DIC) to the subclinical compensated activation of hemostatic factors (nonovert DIC). The first part of this review emphasizes two points. First, activation of the hemostatic system is controlled by a vast network of capillaries and venules through anticoagulant and anti-inflammatory regulatory factors that operate from the endothelium (e.g., protein C and thrombomodulin, tissue factor pathway inhibitor). These hemostatic regulators can be overridden by procoagulant disorders such as amniotic fluid embolism or degraded by proinflammatory disorders such as sepsis. Second, because this link between the microvascular endothelium and circulating hemostatic factors is so close, even a relatively mild disturbance of the microvasculature targeted by the inflammatory process may be reflected systemically by changes in molecular biomarkers of hemostatic activity. Therefore, application of criteria for the diagnosis of nonovert DIC should be of value in detecting a compensated response to inflammatory stress of the microvasculature in patients who are at risk before they develop an uncompensated over DIC response and organ failure. The second part of this review covers the recent experience investigators have had in diagnosing and following the response of patients to treatment with biomarkers.

Biomarkers↗